Immunodysfunction: A Cause of Stealth COVID-19 Illness and Death

The concept of immune dysfunction caused by COVID-19 is rapidly changing from a theoretical construct to a significant adverse outcome of COVID-19. One which may have the potential to collapse our health care system and impact patients long after they become COVID-19-negative.

Recently increases in seasonal influenza and respiratory syncytial virus (RSV) infections have been a major concern. Patients have filled hospitals, and an “Anything But Covid” or “ABC” narrative has been adopted. For many, including a few major federal agencies, the previous year’s masking and social isolation were blamed. This “immune debt” narrative discourages the public from following public health mitigation strategies.
 
The first problem with this narrative is that in 2022, few individuals were masking or avoiding crowded indoor venues.

In addition, in the United States, seasonal influenza affects approximately 9 to 41 million residents a year, about 3 to 12% of the population. Having 1 or 2 years of a low influenza season should not create a significant “immune debt.”

This narrative's second major problem is that we had a large RSV wave last year. Other countries, such as Germany, also saw a large RSV hospital filling surges this year after a significant surge the year before. The same pattern was observed in Sweden, a country known for its openness during the COVID-19 pandemic and its almost total lack of masking. A nonpeer-reviewed study posted on medRxiv found that 19.2% of RSV-infected children had documented COVID-19 infections compared to only 9.7% of children uninfected with RSV.
 
Now increasing reports are coming from the United Kingdom and the United States of an increase in dangerous group A streptococcal infections afflicting children and adults. In the United Kingdom, there were 27,486 notifications of scarlet fever (a severe manifestation of group A streptococcal infections) from Sept. 19, 2022, to Jan. 8, 2023, compared to 3,287 during the last comparably high season in 2017 to 2018. In a large study regarding outcomes from mild SARS-CoV-2 infections published in the BMJ, it was observed that COVID-19 patients were 34% more likely to have Strep tonsillitis than comparable controls. This finding was described as a “low but significant excess risk” of infection.

Aspergillus fumigatus, a fungus the lungs naturally resist, can become deadly in patients with severe SARS-CoV-2. COVID-19 can cause 2 types of white blood cells (neutrophils and B cells) to not work together allowing for rapid spread and invasion of the fungus.
 
And in China, with a newly surging pandemic, 3% of patients are reported to have reinfections attributed to “damage done to the immune system by the first infection with COVID-19.”
 
Reactivation of herpes simplex, herpes zoster, and Epstein-Barr virus have also been observed with COVID-19. This reactivation probably results in a drop in immune surveillance. The reactivation of the Epstein-Barr virus is thought to be one of the causes of long COVID.

Finally, there is abundant laboratory evidence of immunodysfunction after COVID-19. Anthony Leonardi, PhD, MS, Johns Hopkins Bloomberg School of Public Health and Rui B. Proenca, PhD, Department of Biology, Johns Hopkins University, first described aberrant T cell differentiation and lymphopenia in severe COVID-19. The authors stated: “These facets depict SARS-Cov-2 as a lympho-manipulative pathogen; it distorts T cell function, numbers, and death, and creates a dysfunctional immune response.” SARS-CoV-2 can infect lymphocytes through ACE2-independent receptor (LFA-1) and cause a “marked lymphopenia in severe patients.”

A study published in Nature Immunology reported laboratory data and findings that documented immune dysfunction for up to 8 months (the longest time period studied) in individuals with long COVID. These individuals were described as having “highly activated innate immune cells and lacked naïve T and B cells.” P. Chattopadhyay, PhD, et al have reported an impairment in the B-cell maturation process and an absent subset of naïve T-cells in COVID-19-recovered patients, which is present in healthy individuals. Jacob K. Files, MD, et al also found that “data suggest a prolonged period of immune dysregulation after SARS-CoV-2 infection” and that “many of these changes were found to increase over time in nonhospitalized longitudinal samples, suggesting a prolonged period of immune dysregulation after SARS-CoV-2 infection.” Cong-Ying Song, PhD, et al described immune dysfunction following COVID-19 and found that this “...dysfunction plays critical roles in disease progression.”
 
Along with heart disease, immune dysfunction and severe infections are becoming another cause of stealth COVID-19 deaths. The public needs a paradigm shift from believing that COVID-19 is a respiratory disease to understanding that COVID-19 impacts every organ of the body, causing delayed manifestations such as strokes, heart attacks, and infections which can present long after one becomes COVID-19-negative. The impact of these delayed effects can almost double the COVID-19-associated fatalities and is responsible for the increase in excess deaths, which exceeds the number of officially reported COVID-19 deaths. Federal policymakers must focus on mitigating the spread of this disease, and the public must embrace high-quality well-fitted masking (N95) along with vaccinations and boosters. Otherwise, recurrent infections over one’s lifetime may be a winning strategy for the virus.